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Interleukin-4 (IL-4) is an anti-inflammatory cytokine, which can be protective in inflammatory and neurological disorders, and can alleviate pain. Classically, IL-4 diminishes pain by blocking the production of pro-inflammatory cytokines. Here, we uncovered that IL-4 induces acute antinociception by IL-4 receptor α (IL-4Rα)-dependent release of opioid peptides from M1 macrophages at injured nerves. As a model of pathological pain we used a chronic constriction injury (CCI) of the sciatic nerve in male mice. A single application of IL-4 at the injured nerves (14 days following CCI) attenuated mechanical hypersensitivity evaluated by von Frey filaments, which was reversed by co-injected antibody to IL-4Rα, antibodies to opioid peptides such as Met-enkephalin (ENK), β-endorphin and dynorphin A 1-17, and selective antagonists of δ-, µ- and κ-opioid receptors. Injured nerves were predominately infiltrated by pro-inflammatory M1 macrophages and IL-4 did not change their numbers or the phenotype, assessed by flow cytometry and qRT-PCR, respectively. Macrophages isolated from damaged nerves by immunomagnetic separation and stimulated with IL-4 dose-dependently secreted all three opioid peptides measured by immunoassays. The IL-4-induced release of ENK was diminished by IL-4Rα antibody, intracellular Ca chelator, and inhibitors of protein kinase A (PKA), phosphoinositide 3-kinase (PI3K), and ryanodine receptors. Together, we identified a new opioid mechanism underlying the IL-4-induced antinociception that involves PKA-, PI3K-, ryanodine receptor-, and intracellular Ca-mediated release from M1 macrophages of opioid peptides, which activate peripheral opioid receptors in injured tissue.Interleukin-4 (IL-4) is an anti-inflammatory cytokine, which can ameliorate pain. The IL-4-mediated effects are considered to mostly result from the inhibition of the production of pro-inflammatory mediators (e.g., IL-1β, tumor necrosis factor, prostaglandin E2). Here, we found that IL-4 injected at the injured nerves attenuates pain by releasing opioid peptides from the infiltrating macrophages in mice. The opioids were secreted by IL-4 in the intracellular Ca-dependent manner and activated local peripheral opioid receptors. These actions represent a novel mode of IL-4 action, since its releasing properties have not been so far reported. Importantly, our findings suggest that the IL-4-opioid system should be targeted in the peripheral damaged tissue, since this can be devoid of central and systemic side effects.
Learn More >Gα-coupled receptors signaling through cAMP provide a key mechanism for the sensitization of nociceptive sensory neurons, and the cAMP effector Epac has been implicated in the transition from acute to chronic pain. Epac exerts its effects through Rap1 and protein kinase C (PKC). To identify targets of Epac-PKC signaling in sensory neurons of the mouse dorsal root ganglion (DRG), we profiled PKC substrate proteins phosphorylated in response to activation of Epac with the pro-inflammatory prostaglandin PGE2. A prominent Epac-dependent phospho-protein band induced by PGE2 was identified by mass spectrometry as the mitochondrial enzyme pyruvate dehydrogenase (Pdha1). In dissociated DRG from both males and females, recruitment of Pdha1 to phospho-protein fractions was rapidly induced by PGE2 and prevented by selective inhibition of Epac2. Epac activation increased mitochondrial respiration, consistent with an increase in Pdha1 function mediated by Epac2. Hindpaw injection of PGE2 induced heat hyperalgesia in males and females, but Pdha1 phosphorylation occurred only in males. Hyperalgesia was attenuated in males but not females by systemic inhibition of Epac2, and also by a mitochondrial membrane potential uncoupler, dinitrophenol, supporting a role for mitochondrial regulation in acute hyperalgesia. These findings identify a mechanism for the regulation of mitochondrial function by Epac2 that contributes to acute inflammatory hyperalgesia in male mice. Systemic administration of the COX2 inhibitor celecoxib suppressed both PGE2-induced heat hyperalgesia and Pdha1 phosphorylation in DRG of males but not females, suggesting that prostaglandin synthesis within the DRG mediates the phosphorylation of Pdha1 in response to hindpaw insult.There has been extensive investigation of mitochondrial dysfunction as a causative factor in neuropathic pain disorders. In contrast, results reported here implicate enhanced mitochondrial function as a contributing factor in the development of acute inflammatory hyperalgesia. We describe a mechanism in which Epac2 activation by prostaglandin receptors leads to phosphorylation of pyruvate dehydrogenase and an increase in mitochondrial respiration in peripheral sensory neurons. Although Epac2 activation leads to Pdha1 phosphorylation in dissociated neurons from mice of both sexes, induction of this pathway by hindpaw insult is restricted to males and appears to require intra-ganglionic prostaglandin synthesis. These findings support a model in which Gs-coupled receptor modulation of mitochondrial function promotes acute nociceptive signaling and inflammatory hyperalgesia.
Learn More >Baroreceptors are mechanosensitive elements of the peripheral nervous system that maintain cardiovascular homeostasis by coordinating the responses to external and internal environmental stressors. While it is well known that carotid and cardiopulmonary baroreceptors modulate sympathetic vasomotor and parasympathetic cardiac neural autonomic drive, to avoid excessive fluctuations in vascular tone and maintain intravascular volume, there is increasing recognition that baroreceptors also modulate a wide range of non-cardiovascular physiological responses via projections from the nucleus of the solitary tract to regions of the central nervous system, including the spinal cord. These projections regulate pain perception, sleep, consciousness, and cognition. In this article, we summarize the physiology of baroreceptor pathways and responses to baroreceptor activation with an emphasis on the mechanisms influencing cardiovascular function, pain perception, consciousness, and cognition. Understanding baroreceptor-mediated effects on cardiac and extra-cardiac autonomic activities will further our understanding of the pathophysiology of multiple common clinical conditions, such as chronic pain, disorders of consciousness (e.g., abnormalities in sleep-wake), and cognitive impairment, which may result in the identification and implementation of novel treatment modalities. © 2021 American Physiological Society. Compr Physiol 11:1373-1423, 2021.
Learn More >The aetiology of primary chronic pain syndromes (CPS) is highly disputed. We performed a systematic review and meta-analysis aiming to assess differences in circulating cytokines levels in patients with diffuse CPS (fibromyalgia) versus healthy controls (HC).
Learn More >Monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor are a key achievement in the field of migraine prevention, being the first migraine-specific preventatives. Several characteristics distinguish monoclonal antibodies targeting the CGRP pathway from the previously available drug classes for migraine prevention, including their specificity, their monthly or quarterly subcutaneous administration, and their rapid onset of action.
Learn More >To examine the benefits of an integrated psychosocial group treatment (IPGT) model for patients with chronic pain at risk of opioid misuse.
Learn More >Acute neuropathic pain is a significant diagnostic challenge, and it is closely related to our understanding of both acute pain and neuropathic pain. Diagnostic criteria for acute neuropathic pain should reflect our mechanistic understanding and provide a framework for research on and treatment of these complex pain conditions.
Learn More >Given efforts to reduce opioid use, and because marijuana potentially offers a lower-risk alternative for treating chronic pain, there is interest in understanding the public health impact of marijuana legalization on opioid-related outcomes.
Learn More >Microsomal prostaglandin E2 synthase 1 (mPGES-1) is recognized as a promising target for a next generation of anti-inflammatory drugs that are not expected to have the side effects of currently available anti-inflammatory drugs. Lapatinib, an FDA-approved drug for cancer treatment, has recently been identified as an mPGES-1 inhibitor. But the efficacy of lapatinib as an analgesic remains to be evaluated. In the present clinical data mining (CDM) study, we have collected and analyzed all lapatinib-related clinical data retrieved from clinicaltrials.gov. Our CDM utilized a meta-analysis protocol, but the clinical data analyzed were not limited to the primary and secondary outcomes of clinical trials, unlike conventional meta-analyses. All the pain-related data were used to determine the numbers and odd ratios (ORs) of various forms of pain in cancer patients with lapatinib treatment. The ORs, 95% confidence intervals, and P values for the differences in pain were calculated and the heterogeneous data across the trials were evaluated. For all forms of pain analyzed, the patients received lapatinib treatment have a reduced occurrence (OR 0.79; CI 0.70-0.89; P = 0.0002 for the overall effect). According to our CDM results, available clinical data for 12,765 patients enrolled in 20 randomized clinical trials indicate that lapatinib therapy is associated with a significant reduction in various forms of pain, including musculoskeletal pain, bone pain, headache, arthralgia, and pain in extremity, in cancer patients. Our CDM results have demonstrated the significant analgesic effects of lapatinib, suggesting that lapatinib may be repurposed as a novel type of analgesic.
Learn More >Non-medical prescription opioid use (NMPOU) is at the heart of the opioid epidemic in the United States. Although chronic opioid use is commonly accompanied by deficits in social functioning, little is known about the impact of chronic NMPOU on social cognitive functions. Social neuroscience models suggest that empathy activates similar or even equivalent neural structures as those underpinning the first-hand experience in that emotional state (e.g., pain). Therefore, we measured subjective and psychophysiological responses during an empathy-for-pain task in 23 individuals with NMPOU, objectively confirmed by hair and urine testing, and compared them with 29 opioid-naïve healthy controls. NMPOU individuals showed lower other-related and self-related unpleasantness ratings when seeing others in pain than controls. No differences between the control and NMPOU group were found in skin conductance responses and heart rate variability (HRV) assessed by root mean square of successive differences (RMSSD) in response to the task. However, RMSSD-HRV was strongly negatively correlated with self-related unpleasantness and craving in the NMPOU group. A subsequent mediation analysis showed a total effect of RMSSD-HRV on self-related unpleasantness with no mediation of craving. This indicates that stronger emotion regulation indexed by high RMSSD-HRV might have downregulating effects on sharing others' pain in NMPOU individuals but not in healthy controls, which was further accompanied by decreased ratings of personal distress and empathetic concern. These results contribute to a better understanding of social functioning in chronic opioid users, suggesting adequate emotion regulation and empathy trainings as therapeutic targets for future interventions of opioid use disorders and long-term pain treatment with opioids.
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